D409H GBA1 mutation accelerates the progression of pathology in A53T α-synuclein transgenic mouse model

Donghoon Kim, Heehong Hwang, Seulah Choi, Sang Ho Kwon, Suhyun Lee, Jae Hong Park, Sang Min Kim, Han Seok Ko

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Heterozygous mutations in glucocerebrosidase 1 (GBA1) are a major genetic risk factor for Parkinson's disease and Dementia with Lewy bodies. Mutations in GBA1 leads to GBA1 enzyme deficiency, and GBA1-associated parkinsonism has an earlier age of onset and more progressive parkinsonism. To investigate a potential influence of GBA1 deficiency caused by mutations in GBA1 on the disease progression of PD, GBA1 mice carrying D409H knock-in mutation were crossbred with the human A53T (hA53T) α-synuclein transgenic mice. Here, we show that GBA1 enzyme activity plays a significant role in the hA53T α-synuclein induced α-synucleinopathy. The expression of D409H GBA1 markedly shortens the lifespan of hA53T α-synuclein transgenic mice. Moreover, D409H GBA1 expression exacerbates the formation of insoluble aggregates of α-synuclein, glial activation, neuronal degeneration, and motor abnormalities in the hA53T α-synuclein transgenic mice. Interestingly, the expression of D409H GBA1 results in the loss of dopaminergic neurons in the substantia nigra pars compacta of hA53T transgenic mice. Taken together, these results indicate that GBA1 deficiency due to D409H mutation affects the disease onset and course in hA53T α-synuclein transgenic mice. Therefore, strategies aimed to maintain GBA1 enzyme activity could be employed to develop an effective novel therapy for GBA1 linked-PD and related α-synucleinopathies.

Original languageEnglish (US)
Pages (from-to)32
Number of pages1
JournalActa neuropathologica communications
Issue number1
StatePublished - Apr 27 2018
Externally publishedYes


  • D409H GBA1 mutation
  • Gaucher’s disease
  • Glucocerebrosidase 1
  • Parkinson’s disease
  • α-synuclein

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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